重组甘精胰岛素注射液的人体药代动力学、药效学及生物等效性研究

Studies of pharmacokinetic,pharmacodynamic properties and bioequivalence of recombinant insulin glargine injection in healthy man

目的以低精蛋白重组人胰岛素注射液(诺和灵N)作为参比制剂,评价重组甘精胰岛素注射液国产制剂(长秀霖)和进口制剂(来得时)的生物等效性。方法采用随机、单盲、单中心、交叉设计方法对16名健康男性志愿者进行长秀霖和来得时试验,其中6名接受诺和灵N试验。受试者皮下注射胰岛素(0.4 U/kg)后24h内,以葡萄糖钳夹技术维持受试者血糖在5.0 mmol/L左右。结果与皮下注射诺和灵N相比,皮下注射长秀霖和来得时后,试验中葡萄糖输注率及血清胰岛素浓度在2～4h内迅速上升达到平台期,至注射后24h仍保持较平稳,无明显峰值。长秀霖和来得时组试验中葡萄糖输注率最大值(P<0.01)和血清胰岛素浓度最大值(P<0.05)均明显低于诺和灵N组。经交叉试验设计的多因素方差分析表明,皮下注射长秀霖和来得时组间主要药代动力学参数INS-AUC_(0～24h)、INS-C_(max)差异均无统计学意义(P>0.05)。T_(max)经非参数检验法的秩和检验差异无统计学意义(P>0.05)。经双单侧t检验及90%CI计算,Ln(AUC_(0～24h))的90%CI(82.0%～105.2%)为80%～125%,Ln(C_(max))的90%CI(78.9%～107.7%)为70%～143%。结论长秀霖和来得时均比诺和灵N具有更平稳的降糖效应和更平稳的血清胰岛素浓度,药效学和药代动力学参数统计分析结果表明长秀霖与来得时具有生物等效性。

Objective To study the pharmacokinetic and pharmacodynamic properties of the subcutaneously injected long-acting insulin analog- recombinant insulin glargine injections in comparison with those of reference preparation-NPH insulin injection（Novolin N）in healthy volunteers, and to evaluate the bioequivalence of domestic （BasalinTM） and imported （Lantus） recombinant insulin glargine injection preparation. Methods This single-center, randomized, single-blind, three-period, crossover design study was carried out by an euglycemic glucose clamp test. 16 healthy mate volunteers received single subcutaneous injection of 0.4 U/kg body weight of BasalinTM, Lantus, or Novolin N. BasalinTM and Lantus were administrated in all 16 healthy male volunteers, and Novolin N was administrated to only 6 of them. The necessary glucose infusion rates（GIR）to keep blood glucose concentrations constant at 5.0 mmol/L were determined over a 24-hour period after administration. Results The two injections of insulin glargine did not induce the pronounced peak in metabolic activity（P〈 0.01）and serum insulin concentrations （P〈 0. 05） showed a constant metabolic activity over 24-hour study period, which were different from NPH insulin. The statistic analysis of variance, two one-sided t tests and 90% confidence interval were calculated. There were no significant differences in IN.S-AUC0-24h, INS-Cmax and INS-Tmax between the two glargine insulin preparations （P〈 0.05）. The 90 % confidence interval of BasalinTM-Ln（AUC0-24h）was 0.82 to 1.05 in the range of 0.8 to 1.25, the 90% confidence interval of BasalinTM-Ln （Cmax）was 0. 789 to 1. 077 in the range of 0.7 to 1.43,which were in accordance with those of Lantus. Conclusions The subcutaneously injected long-acting insulin analog-recombinant insulin glargine injections （BasalinTM and Lantus） induce a smoother metabolic effect and more stable serum insulin concentrations than do the NPH insulin injection（Novolin N）. The results of pharmacokinetic and pharmacodynamic properties demonstrate that the domestic （BasalinTM） and imported （Lantus） insulin glargine injection preparations were bioequivalent.